Tumour new-born blood vessel specific binding polypeptide CRGDC and novel recombinant tumor necrosis factor nrhTNF fusion protein and their preparation method

A technology of tumor neovascularization and tumor necrosis factor, applied in the field of medicine and biology, can solve the problem of no obvious inhibition of natural tumor necrosis factor, achieve the effect of reducing clinical drug dosage, reducing toxic and side effects, and improving dose-effect ratio

Inactive Publication Date: 2006-05-10
FOURTH MILITARY MEDICAL UNIVERSITY
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Problems solved by technology

Second, tumor vascular cells are normal cells that enter the tumor from normal tissues, have a stable genome, and are not prone to multiple drug resistance like tumor cells
Anti-CD13 monoclonal antibody can significantly inhibit the tumor suppressor activity of CNGRC-TNF in vivo, making it reach the same level as natural tumor necrosis factor; but has no obvious inhibitory effect on natural tumor necrosis factor

Method used

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  • Tumour new-born blood vessel specific binding polypeptide CRGDC and novel recombinant tumor necrosis factor nrhTNF fusion protein and their preparation method
  • Tumour new-born blood vessel specific binding polypeptide CRGDC and novel recombinant tumor necrosis factor nrhTNF fusion protein and their preparation method
  • Tumour new-born blood vessel specific binding polypeptide CRGDC and novel recombinant tumor necrosis factor nrhTNF fusion protein and their preparation method

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[0133] The applicant selected a cyclic peptide CGRDC containing five amino acids that can specifically bind to αvβ3 integrin, applied gene recombination method, fused it to the amino terminal of nrhTNF, and obtained expression in Escherichia coli. On the basis of successfully constructing and expressing the fusion gene, a low-cost purification process was established with reference to the purification method of nrhTNF. In the in vitro killing test, the fusion protein RGD-nrhTNF has a dose-dependent and obvious killing effect on L929 cells, and the specific activity reaches 5.7×10 8 IU / mg. In animal tumor models, the fusion protein RGD-nrhTNF has a significant inhibitory effect on mouse S180 ascites tumor (tumor inhibition rate is 84.84%), which is significantly higher than the same dose of nrhTNF (tumor inhibition rate is 59.09%). And the side effects are lower than nrhTNF. Although we have no direct evidence to prove that RGD-nrhTNF can enrich the new recombinant human tumo...

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Abstract

The invention discloses the CNGRCVSGCAGRC-nrhTNF fusion protein and their preparation method, comprising the following steps: removing the 1-7 amino acid at the end of tumor necrosis factor amidogen, transforming the 8-10 amino acid into the Arg-Lys-Arg, transforming the 157 amino acid at the end of carboxy group into the phenylalanine, constructing the highly effective and low toxicity nrhTNF, selecting the CRGDC which is screened from bacteriophage exhibit library and highly effectively integrated with ª‡vª‰3 integrin specificity, fusing it into the end of amido of nrhTNF by utilizing the gene engineering method. The CRGDC-nrhTNF fusion protein can concentrate at the tumour newborn vessel, improve the therapeutic specificity of tumor necrosis factor, decrease the whole body dosage, reduce the secondary reaction and improve the quality efficiency ratio.

Description

technical field [0001] The invention belongs to the field of medical biotechnology, and specifically relates to gene cloning, gene mutation, expression of exogenous gene in prokaryotic cells, purification of target protein, tumor neovascularization-specific binding polypeptide and novel recombinant human tumor necrosis factor (nrhTNF) fusion protein In vivo and in vitro activity determination and identification of physical and chemical properties. It further relates to the fusion protein of tumor neovascularization-specific binding polypeptide CRGDC and novel recombinant human tumor necrosis factor (nrhTNF) and its preparation method, and the fusion protein of tumor neovascularization-specific binding polypeptide CRGDC and novel recombinant human tumor necrosis factor (nrhTNF) as an anti-tumor The drug can specifically act on neovascular endothelial cells and tumor cells of tumor tissue. Background technique [0002] 2.1 Tumor necrosis factor related...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K19/00A61P35/00C12N15/09
Inventor 张英起颜真王慧
Owner FOURTH MILITARY MEDICAL UNIVERSITY
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